The allergic asthma phenotype is affected by CD4+ T helper cell-produced cytokines, with severe clinical asthma and mouse models of severe disease associated with IL-17 production, neutrophilia, and glucocorticoid resistance. We demonstrate that Serum Amyloid A (SAA), an endogenous mediator produced by the airway epithelium, induces innate immune cytokine production, neutrophilia, and polarizes Th17 responses to innocuous inhaled antigens. We have reported that SAA stimulates the extracellular Toll-Like Receptor 2 (TLR2) and the intracellular NOD-like receptor, Nlrp3, which are required for the secretion of IL-1, a Th17- polarizing cytokine. In addition, pharmacologic antagonism of the IL-1 receptor prevents IL-17 production in vitro and IL-1 receptor-deficient (IL-1R-/-) mice do not undergo Th17 polarization in response to SAA3-inducing exposures that promote allergic sensitization to ovalbumin or to combined administration of SAA and ovalbumin. Finally, SAA exacerbates allergen-induced airway hyper-responsiveness to methacholine and enhances airway neutrophilia in allergen sensitized and challenged mice. We hypothesize that pulmonary SAA (SAA3 in mice) is an epithelial-derived endogenous mediator of allergic asthma severity that functions to polarize IL-1-dependent Th17 responses that contribute to severe disease. In Specific Aim 1 we will determine quantitative and qualitative patterns of Saa3 expression and SAA3 production during the development of allergic asthma in mouse models of disease. In Specific Aim 2 we will establish the effects of SAA on the antigen-specific CD4+ T cell adaptive immune response in vitro and in vivo using wildtype and inducible airway epithelial SAA3-secreting mice. We will determine whether SAA3 promotes Th17 polarization, whether the receptors TLR2, Nlrp3, IL-1R, and FPR2 (Formyl Protein Receptor 2, which has been shown to induce leukocyte chemotaxis to SAA) are involved, whether the activity is directly upon T cells, and whether the effect of SAA3 is glucorticoid-sensitive. In Specific Aim 3 we will establish in vivo the necessity (using Saa3 silencing, SAA3 neutralization, and SAA3 knockout mice) and sufficiency (using SAA instillation and inducible SAA3- producing transgenic mice) of SAA3 for augmentation of allergic asthma severity, addressing mechanisms implicated from the previous specific aims by which SAA3 worsens lung physiologic and structural allergic asthma phenotypes, including glucocorticoid responsiveness. Understanding the effect of endogenous mediators on Th17-inducing responses in allergic asthma will provide unprecedented insight into the varied nature of the asthma syndrome and may provide novel targets for the development of therapeutics.